ABSTRACT
In this article, the derivatives of 3-quinoline carboxylic acid were studied as inhibitors of protein kinase CK2. Forty-three new compounds were synthesized. Among them 22 compounds inhibiting CK2 with IC50 in the range from 0.65 to 18.2 µM were identified. The most active inhibitors were found among tetrazolo-quinoline-4-carboxylic acid and 2-aminoquinoline-3-carboxylic acid derivatives.
Subject(s)
Carboxylic Acids/pharmacology , Casein Kinase II/antagonists & inhibitors , Drug Design , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Quinolines/pharmacology , Carboxylic Acids/chemical synthesis , Carboxylic Acids/chemistry , Casein Kinase II/metabolism , Dose-Response Relationship, Drug , Humans , Molecular Docking Simulation , Molecular Structure , Protein Kinase Inhibitors/chemistry , Quinolines/chemical synthesis , Quinolines/chemistry , Structure-Activity RelationshipABSTRACT
The synthesis and in vitro evaluation of 40 new 2-phenylisothiazolidin-3-one-1,1-dioxide derivatives are described. The optimization based on biological screening data and molecular modeling resulted in a 10-fold increase in inhibitory activity compared with previously reported inhibitors of this class and led to the identification of 3-{[2-chloro-4-(1,1-dioxido-3-oxoisothiazolidin-2-yl)benzoyl]amino}benzoic acid, a potent inhibitor of human protein kinase CK2 (ÐC50 = 1.5 µM).
Subject(s)
Adenosine Triphosphate/chemistry , Antineoplastic Agents/chemistry , Casein Kinase II/antagonists & inhibitors , Cyclic S-Oxides/chemistry , Protein Kinase Inhibitors/chemistry , Small Molecule Libraries/chemistry , meta-Aminobenzoates/chemistry , Antineoplastic Agents/chemical synthesis , Casein Kinase II/chemistry , Catalytic Domain , Cyclic S-Oxides/chemical synthesis , Drug Design , Enzyme Assays , High-Throughput Screening Assays , Humans , Molecular Docking Simulation , Oligopeptides/chemistry , Protein Conformation , Protein Kinase Inhibitors/chemical synthesis , Small Molecule Libraries/chemical synthesis , Structure-Activity Relationship , User-Computer Interface , meta-Aminobenzoates/chemical synthesisABSTRACT
In order to find the new potent CK2 inhibitors the 60 derivatives of 2-aminopyrimidinone and their 6-aza-substituted analogs were synthesized and tested in vitro. Among them, the most efficient inhibitor 2-hydroxy-5-[4-(4-methoxyphehyl)-6-oxo-1,6-dihydropyrimidin-2-ylamino] benzoic acid was identified (IC50 = 1.1 µM). The structure--activity relationship study of newly synthesized derivatives was carried out and their binding mode with adenosine triphosphate-acceptor site of CK2 was proposed.
Subject(s)
Aminosalicylic Acids/pharmacology , Aza Compounds/pharmacology , Casein Kinase II/antagonists & inhibitors , Drug Design , Protein Kinase Inhibitors/pharmacology , Pyrimidinones/pharmacology , Aminosalicylic Acids/chemical synthesis , Aminosalicylic Acids/chemistry , Aza Compounds/chemical synthesis , Aza Compounds/chemistry , Casein Kinase II/metabolism , Dose-Response Relationship, Drug , Humans , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyrimidinones/chemical synthesis , Pyrimidinones/chemistry , Structure-Activity RelationshipABSTRACT
Apoptosis signal-regulating kinase 1 (ASK1) has recently emerged as an attractive therapeutic target for the treatment of cardiac and neurodegenerative disorders. The selective inhibitors of ASK1 may become important compounds for the development of clinical agents. We have identified the ASK1 inhibitor among 3H-naphtho[1,2,3-de]quinoline-2,7-diones using receptor-based virtual screening. In vitro kinase assay revealed that ethyl 2,7-dioxo-2,7-dihydro-3H-naphtho[1,2,3-de]quinoline-1-carboxylate (NQDI-1) inhibited ASK1 with a K(i) of 500 nM. The competitive character of inhibition is demonstrated in Lineweaver-Burk plots. In our preliminary selectivity study this compound exhibited strong specific inhibitory activity toward ASK1.
